Abstract:

Objective    To investigate the features of genetic variants of disks large-associated protein 1（DLGAP1） gene for autism spectrum disorders（ASD） in a case control study. Methods     Through Affymetrix cytoscan microarrays，297 single nucleotide polymorphisms（SNPs） covering the DLGAP1 gene were selected and analyzed in ASD patients（n＝24） and non-ASD patients（n＝43）. Results    Twenty statistically significant SNPs with different inheritance models（Allelic Association test，Genotypic Association test including default model，genotypic model，trend model，dominant model，recessive model and Logistic regression） were demonstrated in case-control study. Associations of 9 SNPs with ASDs were significant in all models and strong linkage disequilibriums were found between rs9956191 and rs4797127（D’＝0.93，LOD＝17.08，r2＝0.722）and between rs4797180 and rs8091193（D’＝1.0，LOD＝14.82，r2＝0.0.933）.Further haplotype analysis showed that rs9956191/rs4797127（T-G）was statistically and significantly related to ASDs（Permutation，P＝0.036）. The haplotype rs9956191/rs4797127（T-G）was significantly associated with the three items of social emotional field and three items of field for interest and stereotyped activities in DSM-V. No significant correlation of sensory perception with this haplotype was found. Conclusion    These findings support that the genetic variants of DLGAP1 gene may play a role in ASD.

Key words: autism spectrum disorders, disks large-associated protein 1 gene, microarrays, case control study

摘要：

目的    分析Disks大同源物关联蛋白1（DLGAP1）基因在儿童孤独症谱系障碍（ASD）中的遗传多态性特征。方法    上海交通大学医学院附属上海儿童医学中心2014年7月至2014年9月采用Affymetrix CytoScan基因芯片， 对ASD儿童24例和非ASD儿童43例DLGAP1基因的297个单核苷酸多态性（SNP）进行病例-对照分析。两组资料进行多种模型（等位基因关联检验， 基因型关联检验包括基因型模式、 趋势模型、 显性模型、 隐性模型和Logistic回归）分析。结果    ASD组共发现20个有统计学意义的SNP。其中9个SNP在各模型中均有ASD发生风险， 连锁不平衡分析显示rs9956191和rs4797127（D’＝0.93， LOD＝17.08， r2＝0.722）及rs4797180和rs8091193（D’＝1.0， LOD＝14.82， r2＝0.0933）呈强连锁不平衡。进一步的单体型分析表明， rs9956191/rs4797127（T-G）为ASD的发生风险（置换检验P＝0.036）。该单体型是美国《精神障碍诊断与统计手册》第5版（DSM-Ⅴ）标准中社会情感互动缺陷，社交互动的非言语沟通行为缺陷，发展、维持和理解人际关系缺陷，刻板重复动作或语言，过分坚持常规或仪式化动作，过分狭窄或固定的兴趣6个条目发生风险因素， 而不是感知觉异常的发生风险因素。结论     DLGAP1的遗传变异可能在ASD发病中具有一定作用。

关键词: 孤独症谱系障碍, DLGAP1基因, 基因芯片, 病例对照研究